Polyarteritis nodosa systemic M30.0

Older name for non-granulomatous microscopic polyangiitis. For historical reasons the older name is discussed here again.

Definition: Rare, potentially life-threatening, multi-organ systemic disease with necrotizing vasculitis of medium-sized vessels (no small vessels), rheumatoid general symptoms, abdominal pain, various skin symptoms and signs of arterial occlusive disease (PAD).

Note: In childhood the microscopic polyangiitis cannot be distinguished from the Kawasaki syndrome.

Incidence: Incidences have been decreasing for 20 years. In earlier decades, there were demonstrable associations (about 1/3 of cases) with hepatitis B virus infection. In more recent studies, such associations are found in only about 5% of patients.

The current incidence is 0.1-1.0/100,000 inhabitants/year.

The prevalence is 0.2-3.0/100,000 inhabitants. It is significantly higher with HBsAg (hepatitis B surface antigen) positivity.

Idiopathic (90%). In 5% of cases, HbS antigen is detectable in the blood, sometimes also in the affected vascular segments in the form of immune complexes.

PAN as a result of minocycline ingestion is a very rare event. This constellation can occur with prolonged use of the preparation.

The occurrence of PAN with epididymitis after COVID-19 vaccination is noteworthy (Ohkubo Y et al. 2023).

It is also assumed that ANCA plays an inducing role in triggering the disease in a smaller proportion of patients. However, ANCA is usually negative.

A genetic variant of systemic polyarteritis nodosa is caused by an autosomal recessive mutation in the CECR1 gene and is associated with a deficiency of adenosine deaminase 2 (ADA2).

Mostly occurring in middle age, the majority of patients are > 50 years old at onset. Disease peak: 65th-74th LJ. Men are affected 3 times more frequently than women (these figures refer to a Caucasian population; in other ethnic groups e.g. Persia no gender emphasis).

Systemic manifestations:

• Severe AZ disturbance with fever, weight loss, and/or night sweats.
• Renal involvement (70%): Partial glomerular focal nephritis (proteinuria), risk of uremia. Myalgias (50%), arthralgias (50%).
• Gastrointestinal symptoms (50%): Gastrointestinal ulcerations with colic (involvement of mesenteric vessels).
• Neurological symptoms (80%): Polyneuropathy, convulsions, apoplexy (juvenile stroke).
• Cardiac symptoms (70%): Angina pectoris, pericarditis, myocardial infarction. CNS symptoms (50%):
• Opthalmological symptoms: fundus hypertonicus, vasculitis.
• Orchitis with testicular pain.
• Remark: PAN viscerally affects only medium and small arteries. Capillaries, arterioles and venules are not affected. There is no glomerulonephritis nor involvement of the small pulmonary vessels.

Skin manifestations (50% of cases):

• Skin manifestations occurring in the setting of (primary) systemic PAN with subcutaneous papules or nodules palpable along the course of the artery.
• Livedo racemosa (leading symptom!)
• Atrophy blanche
• Purpura (areal or petechial: no leukocytoclastic vasculitis!)
• Ischemic fingertip necrosis due to digital artery occlusion.
• therapy-resistant ulcers

Increase in inflammatory parameters with high ESR and elevated CRP, leukocytosis (neutrophilia); possibly thrombocytosis;

Look for hepatitis B surface antigens, complement consumption (complement decreased), and antineutrophil antibodies (pANCA).

Note: pANCA are positive in only a small proportion of patients.

Thus, the immunopathogenesis of PAN is heterogeneous.

Degenerative stage: Fibrinoid necrosis of all wall layers of the affected middle artery.

Inflammatory stage: Infiltration with neutrophils, eosinophils, round cells, possibly thrombosis.

Granulomatous stage: granulation tissue.

Fibrotic stage: scarring.

American College of Rheumatology (ARA) criteria for the diagnosis of PAN.

The diagnosis of PAN is made if at least 3 of the criteria apply. The sensitivity of the method is approx. 82%, the specificity approx. 86%.

1. Weight loss > 4 kg bw since onset of disease.
2. Image of livedo "racemosa" on the extremities or trunk.
3. Testicular pain not due to infection, trauma, or other palpable causes.
4. Diffuse myalgias or muscle weakness outside shoulder or pelvis or atrophy of leg muscles.
5. Hypertension with diastole > 90 mm Hg.
6. Mononeuropathy, multiple mononeuropathies, or polyneuropathy.
7. Increase in blood urea > 40 mg/dl or creatinine > 1.5 mg/dl.
8. Detectability of HBsAg or antibodies.
9. Aneurysms or occlusions of abdominal arteries not due to atherosclerosis, fibromuscular dysplasia, or noninflammatory causes.
10. Biopsy: granulocytic or mononuclear infiltrate in the arterial walls of small or medium-sized arteries.

Generally valid therapy schemes cannot be given for this (certainly very heterogeneous) disease. The therapy is applied organ- and activity-adapted (see also table 3).

Continuous glucocorticoid(100-150 mg prednisone equivalent) and cyclophosphamide(Endoxan) therapy(Fauci regimen) is used only in severe systemic vasculitis until stable partial remission has occurred. Subsequently, cyclophosphamide-sparing interval therapy. Alternative: Low-dose therapy with 25-30 mg methotrexate (MTX), i.v. 1 time/week.

Caveat. Cyclophosphamide dose must always be adjusted to renal function; leukocytes: > 3000-3500/μl!

If chronic hepatitis B virus infection is present (HBsAd pos., HBeAg pos., HBV neg., PCR pos.), treatment with interferon alfa and/or lamivudine is also possible.

Intermittent course in phases. Fulminant course with exitus lethalis possible within 1-2 years in 20-30% of cases. Possible healing under glucocorticoid therapy. 5-year survival time without therapy approx. 10-15%, with therapy 80%.

There is currently no firm evidence that cutaneous PAN (cutaneous polyarteritis nodosa) transforms into systemic PAN. Cutaneous polyarteritis nodosa is thus defined as an independent clinical picture with a fundamentally better prognosis.

Recently, a mutation in the CECR1 gene in PAN has been described. This mutation is associated with a significantly reduced activity of adenosine deaminase 2 (ADA 2) and is phenotypically related to the clinical picture of PAN. Pathogenetically it is assumed that the increased adenosine levels are responsible for macrophage activation, consecutive immunodeficiency and thrombotic occlusion of medium-sized vessels (see CECR1 gene below).

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